Pharmacologically active compounds

ABSTRACT

Amidinoformic acids and amidinosulphinic acids which are histamine H 2  -antagonists. A specific compound of this invention is N-[2-(3-(1,2,5)-thiadiazolylmethylthio)ethyl]amidinoformic acid.

This is a division of application Ser. No. 065,478 filed Aug. 10, 1979now U.S. Pat. No. 4,308,275, which is a division of application Ser. No.914,329 filed June 12, 1978 now U.S. Pat. No. 4,189,488, which is adivision of application Ser. No. 773,590 filed Mar. 2, 1977 now U.S.Pat. No. 4,118,502.

This invention relates to pharmacologically active compounds, to methodsfor preparing these compounds, to pharmaceutical compositions containingthese compounds and to methods of blocking histamine H₂ -receptors byadministering these compounds. The compounds of the invention can existas acid addition salts but, for convenience, reference will be madethroughout this specification to the parent compounds.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has a number of biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" of which mepyramine, diphenhydramine andchloropheniramine are examples, are mediated through histamine H₁-receptors (Ash and Schild, Brit. J. Pharmac. Chemother, 27, 427,(1966)), and drugs with this activity are hereinafter referred to ashistamine H₁ -antagonists. However, other of the biological actions ofhistamine are not inhibited by histamine H₁ -antagonists and actions ofthis type which are inhibited by a compound described by Black et al.(Nature, 236, 385, (1972)) and called burimamide are mediated throughreceptors which are defined by Black et al. as histamine H₂ -receptors.Thus histamine H₂ -receptors may be defined as those histamine receptorswhich are not blocked by mepyramine but are blocked by burimamide.Compounds which block histamine H₂ -receptors are referred to ashistamine H₂ -antagonists.

Blockade of histamine H₂ -receptors is of utility in inhibiting thebiological actions of histamine which are not inhibited by histamine H₁-antagonists. Histamine H₂ -antagonists are therefore useful, forexample, as inhibitors of gastric acid secretion, as anti-inflammatoryagents and as agents which act on the cardiovascular system, forexample, as inhibitors of the effects of histamine on blood pressure. Inthe treatment of certain conditions, for example, inflammation and ininhibiting the actions of histamine on blood pressure, a combination ofhistamine H₁ - and H₂ -antagonists is useful.

The compounds of this invention have histamine H₂ -antagonist activityand are useful in the treatment of conditions wherein histamine H₂-antagonists are useful.

The compounds of this invention are represented by the following generalformula: ##STR1## wherein

Het is a nitrogen-containing 5 or 6 membered heterocyclic ring such asimidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, triazoleor thiadiazole, which ring is optionally substituted by lower alkyl,halogen, lower alkoxy, hydroxy, trifluoromethyl, hydroxymethyl or amino;

m is 0, 1 or 2 and n is 2 or 3 provided that the sum of m and n is 3 or4;

Y is sulphur, methylene or oxygen;

R is hydrogen, lower alkyl or Het--(CH₂)_(m) --Y--(CH₂)_(n) -- whereHet, m, n and Y are as defined above;

Q is --CO₂ H or --SO₂ H; and pharmaceutically acceptable salts thereof.

Preferably Het is an imidazole, pyridine, thiazole, isothiazole orthiadiazole ring, which ring is optionally substituted by lower alkyl,halogen, lower alkoxy or hydroxy.

More preferably Het is a 2- or 4-imidazolyl ring optionally substitutedby lower alkyl or halogen, or a 2-pyridyl ring optionally substituted bylower alkyl, (preferably methyl), lower alkoxy, halogen, amino orhydroxy, a 2-thiazolyl ring, a 3-isothiazolyl ring optionallysubstituted by halogen, or a 3-(1,2,5)-thiadiazolyl ring optionallysubstituted by halogen or a 2-(5-amino-1,3,4-thiadiazolyl) ring.

Particularly preferably Het is a 2-thiazolyl, 5-methyl-4-imidazolyl,5-bromo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl,3-methoxy-2-pyridyl or 3-hydroxy-2-pyridyl ring.

Preferably m is 1 and n is 2, and compounds wherein Y is sulphur ormethylene are also preferred. Most preferably Y is sulphur.

Throughout this specification by the term "lower alkyl" we mean an alkylgroup containing from 1 to 4 carbon atoms, and by the term "loweralkoxy" we mean an alkoxy group containing from 1 to 4 carbon atoms.

Some specific preferred compounds which fall within the scope of thepresent invention are:

N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]amidinoformic acid

N-Methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-amidinoformicacid

N-Methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-amidinosulphinicacid

N-Methyl-N'-[2-(2-thiazolylmethylthio)ethyl]amidinosulphinic acid

N-[2-(2-thiazolylmethylthio)ethyl]amidinoformic acid

N-Methyl-N'-[2-thiazolylmethylthio)ethyl]amidinoformic acid.

The compounds of Formula 1 are shown and described as amidinoformic acidand amidinosulphinic acid derivatives. These compounds may also berepresented by many tautomeric structures. Compounds wherein Q is SO₂ Hmay also be referred to as thiourea S,S-dioxides. ##STR2##

Also certain of the heterocyclic rings represented by Het may exist inseveral tautomeric forms, and it will be understood that all thesealternative representations are within the scope of the presentinvention.

Hydrates of compounds of Formula 1 and pharmaceutically acceptablehydrated salts of compounds of Formula 1 are also within the scope ofthis invention.

Compounds of Formula 1 wherein Q is --CO₂ H may be prepared by treatinga compound of Formula 2, wherein R is as defined in Formula 1 and R¹ ishydrogen or an acid-protecting group such as lower alkyl or benzyl, withan amine of Formula 3, wherein Het, m, Y and n are as defined in Formula1, and when R¹ is other than hydrogen, removing the acid-protectinggroup. ##STR3##

Preferably R¹ is hydrogen. Preferably this reaction is carried out in apolar solvent, such as a lower alcohol or water.

The rate of reaction may be increased by the addition of an oxide or asalt of a heavy metal to the reaction mixture. Preferred oxides of heavymetals are trilead tetroxide, mercury (II) oxide and lead (II) oxide.Preferred salts of heavy metals are salts of lead, mercury and silver,and soluble salts such as lead acetate, lead nitrate or silver nitrateare particularly preferred. Preferably the acid protecting group R¹ isremoved under acidic conditions. In an alternative procedure thecompound of formula 2 need not be isolated but may be formed in situ byeither treating a thiooxamate ester with an amine RNH₂, or by treatingpotassium thiooxamate with an amine RNH₂ and subsequent acidification.

Compounds of Formula 1 wherein Q is --CO₂ H may alternatively beprepared by treating a compound of Formula 4 ##STR4## wherein R is asdefined in Formula 1, R¹ is hydrogen or an acid-protecting group such aslower alkyl, and R² is lower alkyl, with an amine of Formula 3 and whenR¹ is other than hydrogen, removing the acid-protecting group.Preferably this reaction is carried out in a dipolar aprotic solventsuch as dimethylformamide or acetonitrile. Preferably theacid-protecting group R¹ is removed under acidic conditions. Thecompounds of Formula 4 may be prepared by alkylation of thecorresponding compounds of Formula 2, for example by treatment with analkyl halide or sulphate.

Thiooxamic acid derivatives of formula Het(CH₂)_(m) --Y--(CH₂)_(n)--NH--CSCO₂ H may be prepared by treating an amine of Formula 3 withpotassium thiooxamate and subsequent acidification.

Compounds of Formula 1 wherein Q is --SO₂ H may be prepared by treatinga thiourea of Formula 5: ##STR5## wherein Het, m, Y, n and R are asdefined in Formula 1, with hydrogen peroxide. Preferably this reactionis carried out under neutral conditions at a temperature in the range of-5° to +10° C. in a solvent such as a lower alcohol.

The compounds of Formula 1 block histamine H₂ -receptors, that is theyinhibit the biological actions of histamine which are not inhibited byhistamine H₁ -antagonists such as mepyramine but are inhibited byburimamide. For example, the compounds of this invention have been foundto inhibit histamine-stimulated secretion of gastric acid from thelumen-perfused stomachs of rats anaesthetised with urethane, at doses offrom 0.5 to 256 micromoles per kilogram intravenously. This procedure isreferred to in the above mentioned paper of Ash and Schild. The activityof these compounds as histamine H₂ -antagonists is also demonstrated bytheir ability to inhibit other actions of histamine which, according tothe above mentioned paper of Ash and Schild, are not mediated byhistamine H₁ -receptors. For example, they inhibit the actions ofhistamine on the isolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastricacid and also that stimulated by pentagastrin or by food.

In addition, in a conventional test such as the measurement of bloodpressure in the anaesthetised cat, the action of the compounds of thisinvention at doses of from 0.5 to 256 micromoles per kilogramintravenously in inhibiting the vasodilator action of histamine can alsobe demonstrated. The level of activity of the compounds of thisinvention is illustrated by the effective dose producing 50% inhibitionof gastric acid secretion in the anaesthetised rat and the doseproducing 50% inhibition of histamine-induced tachycardia in theisolated guinea pig atrium (less than 10⁻⁴ Molar).

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the neutral form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding compound of Formula 1 bystandard procedures, for example by treating the compound with an acidin a lower alkanol or by the use of ion exchange resins to form therequired salt either directly from the neutral compound or from adifferent addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula 1 or a pharmaceutically acceptable acid additionsalt thereof and methods of blocking histamine H₂ -receptors whichcomprise administering a compound of Formula 1 or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 300 mg. If a liquid carrier is used,the preparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid contained for example in an ampoule,or an aqueous or non-aqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the compositions in aneffective amount to block histamine H₂ -receptors. The route ofadministration may be oral or parenteral.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg.

The active ingredient will preferably be administered one to six timesper day. The daily dosage regimen will preferably be from about 150 mgto about 1500 mg.

Advantageously the composition will be made up in a dosage formappropriate to the desired mode of administration for example, as atablet, capsule, injectable solution or as a cream or ointment fortopical application.

The invention is illustrated but in no way limited by the followingexamples wherein all temperatures are in degrees Centigrade:

EXAMPLE 1 N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]amidinoformic acid

Trilead tetroxide (43 g) was added to a solution of thiooxamic acid (4.9g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (8.0 g) in methanol(200 ml). The mixture was stirred at room temperature for 4 hours andfiltered to remove the lead compounds. The product was isolated bycolumn chromatography and trace impurities were removed by boiling inacetonitrile. Dissolving the solid in methanol and precipitation withether yielded N-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amidinoformicacid hemietherate m.p. 174°-176° (decomposition).

(Found: C, 47.2; H, 6.8; N, 20.3; S, 11.3; C₉ H₁₄ N₄ O₂ S 1/2[(C₂ H₅)₂O] requires: C, 47.3; H, 6.8; N, 20.1; S, 11.5%.

EXAMPLE 2N-Methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amidinoformic acidhydrochloride

Trilead tetroxide (50 g) was added to a solution of N-methyl thiooxamicacid (4.7 g) and 2-(5-methyl-4-imidazolylmethylthio) ethylamine (6.0 g)in water (150 ml). The mixture was stirred at room temperature for 2days and then filtered. The filtrate was passed down a column ofAmberlite IRC-50 and the product was eluted with water acidified to pH 3with hydrochloric acid. The water was removed under reduced pressure andthe residue was recrystallised twice from methanol to give the titleproduct (0.7 g) m.p. 158°-159° (decomposition). Elution of the column ofAmberlite IRC-50 with water acidified to pH 3 with hydrobromic acid andevaporation of the water givesN-methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amidinoformic acidhydrobromide.

EXAMPLE 3N-Methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amidinosulphinicacid

N-Methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea (2.93 g)was stirred in methanol (12 ml) with cooling, in an ice bath. 30%Hydrogen peroxide (2.72 g) was added dropwise over 30 min. to give aclear solution which was stored overnight at 0° to yield a white,crystalline solid which was filtered off and dried to give the titleproduct m.p. 120°-121°.

Found: C, 39.0; H, 5.8; N, 20.0; S, 22.8; C₉ H₁₆ N₄ O₂ S₂ requires: C,39.1; H, 5.8; N, 20.3; S, 23.2%.

EXAMPLE 4N,N'-bis-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]amidinoformic acid

2-(5-Methyl-4-imidazolylmethylthio)ethylamine is added to a solution ofpotassium thiooxamate in water. After 2 hours at room temperature thesolution is acidified with hydrochloric acid to yieldN-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]thiooxamic acid. Thisis then reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine andtrilead tetroxide according to the general procedure of Example 2 toyield N,N'-bis-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amidinoformicacid.

EXAMPLE 5 N-[2-(2-Thiazolylmethylthio)ethyl]amidinoformic acid

Substitution of 2-(2-thiazolylmethylthio)ethylamine for2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure ofExample 1 gave the title compound m.p. 152°-154°

Found: C, 39.2; H, 4.5; N, 17.2; S, 26.0; C₈ H₁₁ N₃ O₂ S₂ requires: C,39.2; H, 4.5; N, 17.1; S, 26.1%.

EXAMPLE 6 N-Methyl-N'-[2-(2-thiazolylmethylthio)ethyl]amidinoformic acidhydrochloride

Substitution of 2-(2-thiazolylmethylthio)ethylamine for2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure ofExample 2 leads to the production of the title compound. Treatment ofthe title compound with an excess of sodium carbonate in isopropanol,filtration, treatment of the filtrate with one equivalent of sulphuricacid and evaporation of the mixture givesN-methyl-N'-[2-(2-thiazolylmethylthio)ethyl]amidinoformic acidhemisulphate.

EXAMPLE 7

Substitution of the following thioureas

(a) N-Methyl-N'-[2-(5-ethyl-4-imidazolyl)methylthio)ethyl]thiourea

(b) N-Methyl-N'-[2-(5-bromo-4-imidazolyl)methylthio)ethyl]thiourea

(c)N-Methyl-N'-[2-(5-trifluoromethyl-4-imidazolyl)methylthio)ethyl]thiourea

(d)N-Methyl-N'-[2-(5-hydroxymethyl-4-imidazolyl)methylthio)ethyl]thiourea

(e) N-Methyl-N'-[2-(2-pyridylmethylthio)ethyl]thiourea

(f) N-Methyl-N'-[2-(3-methyl-2-pyridylmethylthio)ethyl]thiourea

(g) N-Methyl-N'-[2-(3-hydroxy-2-pyridylmethylthio)ethyl]thiourea

(h) N-Methyl-N'-[2-(2-thiazolylmethylthio)ethyl]thiourea

(i) N-Methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea

(j) N-Methyl-N'-[2-(4-bromo-3-isothiazolylmethylthio)ethyl]thiourea

(k) N-Methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea

(l)N-Methyl-N'-[2-(5-amino-2-(1,3,4)thiadiazolylmethylthio)ethyl]thiourea

(m) N-Methyl-N'-[2-(2-imidazolyl)ethylthio)ethyl]thiourea

(n) N-Methyl-N'-[3-(2-imidazolylthio)propyl]thiourea

(o) N-Methyl-N'-[3-(2-pyridylthio)propyl]thiourea

(p) N-Methyl-N'-[3-(2-thiazolylthio)propyl]thiourea

(q) N-Methyl-N'-[3-(2-oxazolylthio)propyl]thiourea

(r) N-Methyl-N'-[3-(5-amino-2-(1,3,4)thiadiazolylthio)propyl]thiourea

(s) N-Methyl-N'-[2-(4-imidazolylmethoxy)ethyl]thiourea

(t) N-Methyl-N'-[3-(4-imidazolylmethoxy)propyl]thiourea

for N-methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea inthe procedure of Example 3 leads to the production of the correspondingamidinosulphinic acids.

EXAMPLE 8

Substitution of the following thioureas:

(a) N-Methyl-N'-[4-(4-imidazolyl)butyl]thiourea

(b) N-Butyl-N'-[4-(4-imidazolyl)butyl]thiourea

(c) N-Methyl-N'-[4-(5-bromo-4-imidazolyl)butyl]thiourea

(d) N-Methyl-N'-[4-(5-methyl-4-imidazolyl)butyl]thiourea

(e) N-Methyl-N'-[5-(4-imidazolyl)pentyl]thiourea

(f) N-Methyl-N'-[4-(2-pyridyl)butyl]thiourea

(g) N-Methyl-N'-[4-(2-thiazolyl)butyl]thiourea

(h) N-Methyl-N'-[4-(3-(1,2,4)triazolyl)butyl]thiourea

for N-methyl-N'-[2-(5-methyl-4-imidazolyolmethylthio)ethyl]thiourea inthe procedure of Example 3 leads to the production of the correspondingamidinosulphinic acids

EXAMPLE 9

Substitution of the following thioureas:

(a) N-[2-(4-Imidazolylmethylthio)ethyl]thiourea

(b) N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]thiourea

(c) N-[4-(4-Imidazolyl)butyl]thiourea

for N-methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea inthe procedure of Example 3 leads to the production of the correspondingamidinosulphinic acids.

EXAMPLE 10

Substitution of the following thioureas:

(a) N,N'-bis[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea

(b)N-[2-(2-Pyridylmethylthio)ethyl]-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea

(c) N,N'-bis[4-(4-imidazolyl)butyl]thiourea

for N-methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea inthe procedure of Example 3 leads to the production of the correspondingamidinosulphinic acids.

EXAMPLE 11

Substitution of:

(a) 2-(2-Imidazolylmethylthio)ethylamine

(b) 2-(4-Imidazolylmethylthio)ethylamine

(c) 2-(5-Bromo-4-imidazolylmethylthio)ethylamine

(d) 2-(5-Trifluoromethyl-4-imidazolylmethylthio)ethylamine

(e) 2-(5-Hydroxymethyl-4-imidazolylmethylthio)ethylamine

(f) 2-(2-Pyridylmethylthio)ethylamine

(g) 2-(3-Methyl-2-pyridylmethylthio)ethylamine

(h) 2-(3-Methoxy-2-pyridylmethylthio)ethylamine

(i) 2-(3-Chloro-2-pyridylmethylthio)ethylamine

(j) 2-(3-Amino-2-pyridylmethylthio)ethylamine

(k) 2-(3-Hydroxy-2-pyridylmethylthio)ethylamine

(l) 2-(3-Isothiazolylmethylthio)ethylamine

(m) 2-(4-Bromo-3-isothiazolylmethylthio)ethylamine

(n) 2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamine

(o) 2-(4-Chloro-3-(1,2,5)-thiadiazolylmethylthio)ethylamine

(p) 2-(5-Amino-2-(1,3,4)-thiadiazolylmethylthio)ethylamine

for 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure ofExample 1 leads to the production of:

(a) N-[2-(2-Imidazolylmethylthio)ethyl]amidinoformic acid

(b) N-[2-(4-Imidazolylmethylthio)ethyl]amidinoformic acid

(c) N-[2-(5-Bromo-4-imidazolylmethylthio)ethyl]amidinoformic acid

(d) N-[2-(5-Trifluoromethyl-4-imidazolylmethylthio)ethyl]amidinoformicacid

(e) N-[2-(5-Hydroxymethyl-4-imidazolylmethylthio)ethyl]amidinoformicacid

(f) N-[2-(2-Pyridylmethylthio)ethyl]amidinoformic acid

(g) N-[2-(3-Methyl-2-pyridylmethylthio)ethyl]amidinoformic acid

(h) N-[2-(3-Methoxy-2-pyridylmethylthio)ethyl]amidinoformic acid

(i) N-[2-(3-Chloro-2-pyridylmethylthio)ethyl]amidinoformic acid

(j) N-[2-(3-Amino-2-pyridylmethylthio)ethyl]amidinoformic acid

(k) N-[2-(3-Hydroxy-2-pyridylmethylthio)ethyl]amidinoformic acid

(l) N-[2-(3-Isothiazolylmethylthio)ethyl]amidinoformic acid

(m) N-[2-(4-Bromo-3-isothiazolylmethylthio)ethyl]amidinoformic acid

(n) N-[2-(3-(1,2,5)-thiadiazolylmethylthio)ethyl]amidinoformic acid

(o) N-[2-(4-Chloro-3-(1,2,5)-thiadiazolylmethylthio)ethyl]amidinoformicacid

(p) N-[2-(5-Amino-2-(1,3,4)-thiadiazolylmethylthio)ethyl]amidinoformicacid

Substitution of the above-noted amines for2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedures ofExample 2 and Example 4 leads to the production of the correspondingN-methyl-N'-[2-(heterocyclicmethylthio)ethyl]amidinoformic acids andN,N'-bis-[2-(heterocyclicmethylthio)ethyl]amidinoformic acidsrespectively.

EXAMPLE 12

(i) Reaction of 2-chloro-3-nitropyridine with 2-(2-cyanoethyl)malonicacid diethyl ester and sodium hydride in tetrahydrofuran gives1-(3-nitro-2-pyridyl)-1,1-bis-(carbethoxy)butyronitrile, m.p.93.5°-94.5°, which after alkaline hydrolysis and acidification gives2-(3-cyanopropyl)-3-nitropyridine hydrochloride 142°-145.5°. Reductionwith hydrogen and palladium on charcoal gives3-amino-2-(3-cyanopropyl)pyridine, and treatment of this with sodiumnitrite and sulphric acid and subsequent warming gives2-(3-cyanopropyl)-3-hydroxypyridine. Methylation with methyl iodide andsodium ethoxide in dimethylsulphoxide and subsequent reduction withlithium aluminium hydride gives 4-(3-methoxy-2-pyridyl)butylamine.Reduction of 3-amino-2-(3-cyanopropyl)-3-hydroxypyridine with lithiumaluminium hydride gives 4-(3-amino-2-pyridyl)butylamine. Diazotisationof 4-(3-amino-2-pyridyl)butylamine at pH 1 and treatment with cuprouschloride or cuprous bromide gives 4-(3-chloro-2-pyridyl)butylamine and4-(3-bromo-2-pyridyl)butylamine, respectively.

(ii) Substitution of

(a) 4-(4-imidazolyl)butylamine

(b) 4-(3-methoxy-2-pyridyl)butylamine

(c) 4-(3-chloro-2-pyridyl)butylamine

(d) 4-(3-bromo-2pyridyl)butylamine

(e) 4-(3-amino-2-pyridyl)butylamine

for 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure ofExample 1 leads to the production of:

(a) N-[4-(4-imidazolyl)butyl]amidinoformic acid

(b) N-[4-(3-methoxy-2-pyridyl)butyl]amidinoformic acid

(c) N-[4-(3-chloro-2-pyridyl)butyl]amidinoformic acid

(d) N-[4-(3-bromo-2-pyridyl)butyl]amidinoformic acid

(e) N-[4-(3-amino-2-pyridyl)butyl]amidinoformic acid

EXAMPLE 13

Substitution of

(a) 2-[2-(2-imidazolyl)ethylthio]ethylamine

(b) 3-(4-imidazolylmethylthio)propylamine

(c) 3-(2-imidazolylthio)propylamine

(d) 3-(2-pyridylthio)propylamine

(e) 3-(2-thiazolylthio)propylamine

(f) 5-(4-imidazolyl)pentylamine

for 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure ofExample 1 leads to the production of:

(a) N-[2-(2-(2-imidazolyl)ethylthio)ethyl]amidinoformic acid

(b) N-[3-(4-imidazolylmethylthio)propyl]amidinoformic acid

(c) N-[3-(2-pyridylthio)propyl]amidinoformic acid

(d) N-[3-(2-thiazolylthio)propyl]amidinoformic acid

(e) N-[5-(4-imidazolyl)pentyl]aminidoformic acid

EXAMPLE 14

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N--[2-(5-methyl-4-imidazolylmethylthio)ethyl]-                                amidinoformic acid        150     mg                                          Sucrose                   75      mg                                          Starch                    25      mg                                          Talc                      5       mg                                          Stearic Acid              2       mg                                          ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule

EXAMPLE 15

    ______________________________________                                        Ingredients                 Amounts                                           ______________________________________                                        N--Methyl-N'--[2-(5-methyl-4-imidazolylmethylthio)-                           ethyl]amidinoformic acid hydrochloride                                                                    200 mg                                            Lactose                     100 mg                                            ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

Similarly, the other compounds of Formula 1 may be formulated intopharmaceutical compositions by the procedures of Examples 14 and 15. Thepharmaceutical compositions prepared as in the foregoing examples areadministered to a subject within the dose ranges given hereabove toblock histamine H₂ -receptors.

We claim:
 1. A compound of the formula ##STR6## wherein Het is athiadiazole ring, which ring is optionally substituted by lower alkyl,halogen, lower alkoxy, hydroxy, trifluoromethyl, hydroxymethyl or amino;m is 0, 1 or 2 and n is 2 or 3 provided that the sum of m and n is 3 or4; Y is sulphur, methylene or oxygen; R is hydrogen, lower alkyl orHet--(CH₂)_(m) --Y--(CH₂)_(n) -- where Het, m, n and Y are as definedabove; Q is --CO₂ H or --SO₂ H; or a pharmaceutically acceptable acidaddition salt thereof.
 2. A compound of claim 1 wherein Het is athiadiazole ring, which ring is optionally substituted by lower alkyl,halogen, lower alkoxy or hydroxy.
 3. A compound of claim 1 wherein Hetis a 3-(1,2,5)-thiadiazolyl ring optionally substituted by halogen or a2-(5-amino-1,3,4-thiadiazolyl) ring.
 4. A compound of claim 1 wherein mis 1 and n is
 2. 5. A compound of claim 1 wherein Y is sulphur ormethylene.
 6. A compound of claim 1 wherein Y is sulphur.
 7. Apharmaceutical composition to block histamine H₂ -receptors comprisingas an essential active ingredient in an effective amount to block saidreceptors a compound of claim 1 in combination with a pharmaceuticallyacceptable diluent or carrier.
 8. A pharmaceutical composition of claim7 in tablet or capsule form.
 9. A method of blocking histamine H₂-receptors which comprises administering to an animal in need thereof inan effective amount to block said receptors a compound of claim
 1. 10. Amethod of inhibiting gastric acid secretion which comprisesadministering internally to an animal in need thereof in an effectiveamount to inhibit gastric acid secretion a compound of claim 1.